BEHAVIORAL EFFECTS OF NIGRAL D1 ANTAGONISM

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Considerable evidence indicates that substantia nigra pars reticulata (SNr) acts as an output area for direct and indirect connections originating from several striatal regions. SNr contains a very high concentration of dopamine (DA) D1 receptors, and detailed anatomical studies of the cellular localization of DA receptors have demonstrated that D1 receptors are present on GABA-containing striatonigral terminals in SNr. The proposed research is designed to determine if SNr is an important anatomical site of action for some of the behavioral effects of D1 antagonists. In addition, the proposed research will investigate the interaction between DA and GABA in SNr. It is hypothesized that local injections of the D1 antagonist SCH 23390 into SNr will be highly potent at producing behavioral effects relative to injections in other brain sites. Also, it is hypothesized that D1 antagonism will decrease SNr GABA release as measured by microdialysis, and that the effects of intra-nigral infusions of SCH 23390 will be reversed by co- administration of the GABA-A agonist muscimol. The results of these experiments could help to modify current views on the anatomical and neurochemical basis of the behavioral effects of D1 antagonism, and could expand our knowledge of the behavioral significance of dendritically released DA in SNr . These concepts have important implications for our understanding of the pathophysiological significance of dopamine depletions in Parkinson's disease, and may help to identify novel therapeutic strategies for the treatment of parkinsonian symptoms.